title: Possible metabolic basis for the different immunodeficient states associated with genetic deficiencies of adenosine deaminase and purine nucleoside phosphorylase.
abstract: An inherited deficiency of adenosine deaminase (Ado deaminase; adenosine aminohydrolase, EC 3.5.4.4) causes severe combined immunodeficiency disease in humans. A similar deficiency in purine nucleoside phosphorylase (Puo phosphorylase; purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) engenders a selective cellular immune deficit. To elucidate the possible metabolic basis for the contrasting immunologic phenotypes, we compared the toxicity toward mature resting human lymphocytes of the Ado deaminase substrates deoxyadenosine and adenosine and the Puo phosphorylase substrate deoxyguanosine. When Ado deaminase was inhibited, micromolar concentrations of deoxyadenosine progressively killed nondividing helper and suppressor-cytotoxic T cells, but not B cells. The toxicity required phosphorylation, with subsequent dATP formation. The deoxyadenosine analogs 2-chlorodeoxyadenosine, 2-fluorodeoxyadenosine, and adenine arabinonucleoside also killed resting T cells. Cell death was unrelated to inhibition of adenosylhomocysteinase (EC 3.3.1.1) but was preceded by a gradual decline in ATP levels. As much as 1 mM deoxyguanosine did not impair resting lymphocyte viability, despite the synthesis of dGTP. The combination of 200 microM adenosine plus 500 microM homocysteine thiolactone killed dividing lymphocytes but had no discernible toxic effect toward resting T cells, which accumulated adenosylhomocysteine over a 4-hr period but thereafter excreted the nucleoside into the culture medium. The different clinical syndromes associated with genetic deficiencies of Ado deaminase and Puo phosphorylase may be explained by the ability of dATP to kill mature resting T lymphocytes by depleting ATP levels.
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000633:toxicity; D000243:Adenosine Deaminase / Q000172:deficiency*; D058892:Adenosine Deaminase Inhibitors; D002455:Cell Division; D003839:Deoxyadenosines / Q000633:toxicity; D003841:Deoxycytidine / Q000633:toxicity; D003849:Deoxyguanosine / Q000633:toxicity; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008954:Models, Biological; D009700:Nucleoside Deaminases / Q000172:deficiency*; D010430:Pentosyltransferases / Q000172:deficiency*; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency*
chemical_list: D058892:Adenosine Deaminase Inhibitors; D003839:Deoxyadenosines; D003841:Deoxycytidine; D010430:Pentosyltransferases; D011683:Purine-Nucleoside Phosphorylase; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase; D003849:Deoxyguanosine; D000241:Adenosine